During inflammation, cytokines are secreted by a myriad of cell types in response to endotoxin or other pro-inflammatory stimuli. Exemplary cytokines include tumor necrosis factor (TNF), interferon-gamma (IFN-γ), interleukin-1β (IL-1β) and high mobility group B-1 (HMGB-1). TNF functions as a cell-associated or secreted protein that interacts with a receptor of the TNF receptor family, which in turn communicates with the interior of the cell, with components of TNF receptor associated factors.
The cytokines are important and critical inflammatory mediators of a wide variety of disease states and conditions. For example, TNF-mediated inflammation results in tissue injury, causing a variety of cellular damage, by generating procoagulant activity on endothelial cells (Pober et al., J. Immunol. (1986) 136(5):1680-7), increasing the adherence of neutrophils and lymphocytes (Pober et al., J. Immunol. (1987) 138(10):3319-24), and stimulating the release of platelet activating factor from macrophages, neutrophils and vascular endothelial cells (Camussi et al., J. Exp. Med. (1987) 166(5):1390-404).
Excessive or unregulated TNF production or activity has been implicated in mediating or exacerbating rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases, reperfusion injury, graft v. host rejection, allograft rejections, fever and myalgia due to infection, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS related complex (ARC), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis and psoriasis.
For example, to expand on a specific cytokine-mediated condition, disseminated bacterial infection causes sepsis, a catastrophic clinical syndrome that develops in 750,000 people, and is associated with mortality in about 30% of those affected. (Angus et al., Crit. Care Med., (2001) 29(7):1303-10.) Antibiotics can eradicate infection, but mediators released systemically by the innate immune system mediate the characteristic signs of sepsis, including microvascular hyperpermeability, coagulopathy, organ failure, tissue injury and lethal shock. (Marshall et al., Crit. Care Med. (2001) 29(7 Supp):S99-106.) Significant advances have been made in understanding the activities and mechanisms of specific immune-derived mediators, and the role of timing in the resultant cytokine cascade. Nonetheless, the development of effective clinical therapeutics for sepsis has been hampered by observations that previously described agents must be given prior to the development of sepsis or very soon after onset of the syndrome in order to improve survival, a scenario that is obviously difficult to apply to typical clinical situations.
The systemic inflammatory mediators of lethal sepsis have “early” and “late” components. TNF is the predominate early mediator of lethal shock and tissue injury; it is released within two hours after the onset of acute infection, and it activates the release of other proinflammatory mediators in a “cytokine cascade.” High mobility group B-1 (HMGB-1), a cytosolic and nuclear protein first identified as a non-chromosomal DNA-binding protein, was recently implicated as a “late” mediator of sepsis-related lethality. HMGB-1 is released by endotoxin-stimulated macrophages, but only after a delay of 12-18 hours; a similar delay in HMGB-1 appearance is observed in the serum of mice during endotoxemia, an experimental model that induces a sepsis-like systemic cytokine response. (Wang et al., Science (1999) 285:248-251.) Anti-HMGB-1 antibodies confer significant protection against delayed endotoxin lethality, even when antibody dosing is initiated at a time after the early cytokine responses have peaked and resolved. (Wang et al., Science (1999) 285:248-251.) Other cytokine activities of HMGB-1 include stimulation of macrophages to release TNF, IL-1β, and other inflammatory products, inducing chemotaxis of smooth muscle cells, and mediating acute lung injury and lethality. (Abraham et al., J. Exp. Med. (2000) 165:2950-2954.)Most drug targets available today are so-called “alarm phase” cytokines, such as TNF and IL-1β, that are released early in the inflammatory response. In the clinical environment, it typically takes many hours to recognize sepsis and institute specific treatment; accordingly, it is not surprising that agents directed against these early proinflammatory cytokines have proved to be ineffective when tested in large clinical trials. (Abraham et al., Lancet (1998) 351(9107):929-33; Fisher et al., JAMA (1994) 271(23):1836-43.)
It would be useful to specifically ameliorate cytokine-mediated inflammatory conditions with a composition that inhibits, suppresses or antagonizes the production or activity of cytokines, both early and late phase mediators.